Project Summary/Abstract Dr. Umar is an anesthesiologist with a Ph.D in cardiovascular medicine who is seeking to become a fully independent, NIH funded physician-scientist investigating the development of pulmonary hypertension (PH) in pre-existing pulmonary fibrosis (PF). The immediate goals of this proposal are to solidify his core knowledge in cardiovascular medicine and update his laboratory and analytic techniques while building his publication record and establishing preliminary data for an R01 application. Dr. Umar's proposed research program seeks to understand the mechanisms of development of PH in pre-existing PF with the discovery of a novel microRNA that likely mediates the transition, with the longer term goal of understanding how this discovery can be translated into a novel therapy for patients. Dr. Umar's mentor, Dr. Mansoureh Eghbali in the Department of Anesthesiology and Perioperative Medicine at UCLA, will be responsible for his scientific development, teaching him the molecular and in vivo and in vitro targeting techniques that have been developed since completion of his postdoctoral training. His co-mentor, Dr. Yibin Wang in the Department of Anesthesiology and Perioperative Medicine at UCLA will help him navigate the many pitfalls associated with establishing independence as a physician scientist. In this effort Dr. Umar will be greatly aided by a committee of mentors, including Dr. Xia Yang, who will help ensure he learns state of the art bioinformatics to tease out the key novel networks involved in transition from PF to PF-PH phenotype. Beyond his active participation in cutting-edge research, Dr. Wang will supplement Dr. Umar's knowledge base through carefully selected coursework at UCLA, focusing on the acquisition of molecular biology and bioinformatics tools, statistical proficiency, grant writing and the ethical conduct of research. Dr. Umar's project proposal seeks to dissect the several new and innovative ideas for advancing our current understanding of the pathobiology of PH in pre-existing PF. He has developed a novel combined animal model of PF associated with PH, that recapitulates findings of human PF-PH. Identification of a novel microRNA, miR- 125b, which is significantly upregulated in the lungs of rats with combined PF-PH, along with specific increase in Snai2, a regulator of endothelial to mesenchymal transition, are key finding in his proposal. The possibility of targeting miR-125b and Snai2 as possible targets for novel therapeutics and the use of bioinformatics approach to identify the key networks mediating the transition from PF to PF-PH represent innovative pre- clinical strategies.